Many of Earth’s microbes remain uncultured and under-studied, limiting our understanding of the functional and evolutionary aspects of their genetic material, which remain largely overlooked in most metagenomic studies¹. Here, we analyzed 149,842 environmental genomes from multiple habitats^(2-6) and compiled a curated catalog of 404,085 functionally and evolutionarily significant novel (FESNov) gene families exclusive to uncultivated prokaryotic taxa. All FESNov families span multiple …